delta5(10)-3,6-diketo androstenes



United States Patent 3,004,045 A -3,6-DIKET0 ANDROSTENES FilippusJohannes Zeelen, Oss, Netherlands, assignor to 0rganon Inc., WestOrange, N.J., a corporation of New Jerse No rawing. Filed Oct. 31, 1960,Ser. No. 65,917 Claims priority, application Netherlands Nov. 12, 1959 4Claims. (Cl. 260397.4)

The invention relates to new A -oestrene compounds and to a process forthe preparation thereof.

A large number of biologically active steroids, both of the IO-methyland of the l9-nor-methyl series, have a A -3-keto-group. This group hasa high stability on account of the conjugation of the two double bondsand will therefore preferably be formed, as appears, Inter alia, fromthe fact that by oxidation of a A -3-hydroxysteroid, for instance, bymeans of the Oppenauer oxidadation, not a A -3-keto-steroid is formedbut a A -3-ketocompound.

To be expected was that said group would be stabilised by the presenceof a 6-keto group in the relative steroid, because in that case the A-3-keto group is conjugated with the double bond between the carbon atom6 and the keto group and consequently forms a triple conjugated system.

A process has been found now for the preparation of new A-3,6-diketo-19-nor-steroids, characterized in thata-3,6-diketo-19-nor-steroid having a double bond between the carbonatoms 4 and 5, or a S-hydroxy group, is respectively treated with anacid in the presence of an a-protonic solvent or a dehydrating agent andafter that, if required, with an acid in the presence of an a-protonicsolvent, in consequence of which the double bond between the carbonatoms 4 and 5 shifts to the 5,l0-posi tion, or the S-hydroxy group issplit off and a double bond is formed between the carbon atoms 5 and 10.

It is not unlikely that, starting from a 5-hydroxy19- nor-steriod, firsta A -steroid compound is formed, which, under the influence of thedehydration medium showing an acid reaction, can be converted into thecorresponding M -compound. If required, the steroid compound in questionis treated, after splitting ofi the S-hydroxy group, with an acid in thepresence of an a-protonic solvent.

The invention particularly relates to the preparation of the new,biologically active compounds of the general formula:

in which R =a hydroxyl or acyloxy group,

R =hydrogen or a saturated or unsaturated hydrocarbon radical with 1-4carbon atoms, or

R and R together=a keto group.

From pharmacological experiments it has appeared that the presentcompounds exercise a progestative and oestrogenic activity, andgonad-inhibiting properties.

The A -3,6-diketo-19-nor-steroids to be used as starting products in thepresent process can be prepared in different manners, for example, byintroducing, in a microbiological manner, a 6-hydroxy group in thecorrespond- "ice ing in 6-p0sition non-substituted compounds and byoxidizing the thus obtained compound to the desired A -3,6-

diketo compound. It is also possible to start from a.

A -3-keto-l9-nor-steroid, by enolacylating it to the corresponding A3-acyloxy compound, reacting it, for exam ple, with perphthalic acid andoxidizing the thus obtained A -3-keto-6-hydroxy compound in any knownmanner.

According to the invention A 3,6-diketo-steroids are converted into thecorresponding M -3,6-diketo-steroids by treating them with an acid inthe presence of an aprotonic solvent. In this reaction both inorganicand organic acids can be used.

By a-protonic solvents are understood solvents having no or only aslight proton-aflinity. In the present process generally those solventsare suitable that have a slighter aflinity for protons than the A-3,6-diketo-steroid itself.

As examples of such solvents are mentioned: hydrocarbons, such asbenzene and toluene and halogenated hydrocarbons, such as chloroform,carbon tetrachloride and chlorobenzene.

Good results were obtained by allowing the A -3,6- diketo-steroid tostand for some time, for example for A to 5 hours, in a moderately acidmedium in the presence of a halogenated hydrocarbon at a lowtemperature, for example 5 to 20 C.

The 3,6-diketo-5-hydroxy steroids to be used in the process according tothe invention can be prepared by converting a A-3-hydroxy-l9-nor-steroid or 3-ester thereof, in any manner known perse, into the 5,6-dihydroxy compound and oxidizing the thus obtainedcompound to obtain the 3,6-diketo-5hydroxy compound. The A -3- hydroxyoracyloxy'l9-nor-steroid compounds to be used in this process are known assuch or can be prepared by enolacylating a A -3-keto-19-nor-steroid andreducing thereupon the double bond between the carbon atoms 3 and 4 byany method known per se.

The 3,6-diketo-5-hydroxy-19-nor-steroids can be converted into thedesired A 3,6-diketo-19-nor-steroids by means of one of the knowndehydrating agents, such as a mineral acid, formic acid or oxalic acid.If after dehydration of the S-hydroxy-steroid the desired A steroid isnot obtained, but the A -3,6-diketo-steroid, the latter must be treatedafter that with an acid in the presence of an a-protonic solvent inaccordance with the conversion described above.

If the 19-nor-steroids prepared in accordance with the,

process of the invention have a secondary or tertiary hyof importance toobtain long-acting esters. Preferably carboxylic acids with 1-30 carbonatoms are used.

As examples of acids to'be used are mentioned: formic acid, acetic acid,propionic acid, butyric acid, valer'ic acid, caproic acid, caprylicacid, capric acid, undecylic acid, lauric acid, tridecylic acid,myristic acid, pentadecylic acid, oleic acid, palmitic acid, stearicacid, arachic acid, behenic acid, lignocen'c acid, cerotic acid,mentanic acid, myricinic acid, tn'methyl acetic acid, diethyl aceticacid, hexahydrobenzoic acid, cyclopentyl propionic acid, cyclohexylpropionic acid, 'cyclohexyl butyric acid, citronelic acid, undecylenicacid, erucic acid, benzoic acid, phenyl acetic acid, phenyl propionicacid, phenyl butyric acid, phenyl propiolic acid, succinic acid,glutaric acid, pimelic acid, tartaric acid, carbamic acid, glycine andalanine.

The preparation of these esters can take place in any manner known perse by reaction of the 17-hydroxysteroid with the acid in question, orthe anhydride or.

Example I To a suspension of 25 g. of l7a-methyl-19-nor-testosterone in100 ml. of dioxane are added 50 ml. of acetic acid anhydride and 250 mg.of dinitrobenzene sulphonic g. of this compound are dissolved in 250 ml.of'

ethanol, after which a solution of 9 g. of sodium borohydride in 250 ml.of 70% ethanol is added. The mixture is stirred for two hours at roomtemperature, poured out into water and extracted with chloroform. Thechloroform layer is separated, Washed and dried and evaporated todryness. By chromatography over silicagel and crystallisation from amixture of ether and petroleum ether there is obtained 3.2 g. of the A-3-hydroxy-l7- acetoxy-l7a-methyl-l9-nor-androstene; melting point 143-146 C. and [a] =+9 (chloroform).

A solution of 2 g. of this compound in 2 ml. of pyridine and 1 ml. ofacetic acid anhydride is kept at room temperature for 15 hours, afterwhich 2 ml. of ice water are added. Next the reaction mixture is stirredfor 1 hour, then poured into 100 ml. of water and extracted withmethylene chloride. The extract is washed with 2 N hydrochloric acid,then with l N sodium hydroxide and water, next dried with sodiumsulphate and finally evaporated to dryness. The residue isrecrystallised from aqueous methanol to obtain the A-3,17-diacetoxy-1-7amethyl-19-nor-androstene.

To a solution of 1.38 g. of this compound in 135 ml. of formic acid 1.6ml. of hydrogen peroxide are added, after which the reaction mixture isleft to stand for one night at room temperature and then poured out into750 ml. of Water. The precipitate formed is filtered off, dried andcrystallised from a mixture of benzene and petroleum ether to obtain the3,5,6,l7-tetrahydroxy-17a-methyl-19-nor-androstane-S,l7-diacetate-6-formate.

1.35 g. of this compound are added to a'mixture of 75 ml. of methanol,0.45 g. of sodium carbonate. and 0.4 ml. of water, after which thismixture is stirred for one night at room temperature and then evaporatedin vacuo till nearly dry. The residue is poured out into 100 ml. of icewater, after which the crystals formed are filtered off and dried.

A solution of 1 g. of this compound in 100 ml. of acetone is cooled toC., after which 1.9 ml. of 2.4 N chromic acid are added. After standingsome time the mixture is poured out into water, extracted with methylenechloride, Washed and dried. The methylene chloride extract is evaporatedto dryness and the residue crystallised from ethanol to obtain the3,5,17-trihydroxy-6-keto- 17a-methyl-19-nor-androstane-3,17-diacetate.

l g. of this compound is dissolved in 50 ml. of methanol, after which1.3 g. of potassium hydroxide in 10 ml. of water are added. The mixtureis left to stand for one night at room temperature, after which it ispoured into 100 ml. of water and extracted with chloroform. The extractis evaporated to dryness, after which the residue is suspended in 150ml. of acetone. To this suspension 2 ml. of 2.4 N chromic acid are'addedat 10 C., after which it is poured out into water, extracted withmethylene chloride, washed and dried. The extract is then evaporated todryness, after which the residue is crystallised from a mixture ofchloroform and petroleum ether to obtain the3,6-diketo-5-hydroxy-17-acetoxy-l7ozmethyl-l9-nor-androstane.

0.8 g. of this compound is then dissolved in 80 ml. of chloroform, afterwhich for one hour, at 0 C., HCl-gas is bubbled through the solution.Next the mixture is washedwith water, dried with sodium sulphate andevap- IOH O To a solution of 1.5 g. of3,5,6,17-tetrahydroxy-17amethyl-19-nor-androstane-3,17-diacetate,prepared in accordance with the process of Example I, in m1. oftetrahydro furan, 7.8 g. of lithium aluminum hydride in 450 ml. oftetrahydro furan are added, after which the mixture is refluxed for onehour, cooled and after that treated with ethyl acetate in order todecompose the excess of hydride. Next a saturated solution of sodiumsulphate is added to the mixture and after that anhydrous sodiumsulphate, after which the mixture is filtered off. The filtrate isevaporated to dryness and the residue crystallised from a mixture ofmethanol and petroleum ether to obtain the3,5,6,17-tetrahydroxy-l7a-methyl-19- nor-androstane.

In accordance with the manner described in Example I this compound isconverted into the A -3,6-diketo-1713-hydroxy-lh-methyl-l9-nor-androstene.

To a solution of 0.8 g. of this compound in 2.5 ml. of pyridine 0.58 g.of undecylenic acid chloride are added dropwise at 0 C. The mixture iskept at room temperature for 12 hours and after that heated on asteam-bath for 30 minutes. The mixture is then cooled, poured out into20 ml. of ice water and extracted with ether. The ether extract iswashed with 2 N hydrochloric acid, after that with 1 N sodium hydroxide,then dried with sodium sulphate and finally evaporated to dryness. Theresidue is recrystallised from methanol to obtain the l7-undecylenate ofA -3,6-diketo-17p-hydroxy-17a-methyl-19- nor-androstene.

Analogously the hexahydrobenzoate, the 17,3-phenyl propionate, theoleate and the pentadecylate are prepared.

In accordance with the process described in this example the A-3,6-diketo-17fi-hydroxy-l7a-propyl-19- nor-androstene and the A-3,6-diketo-17fi-hydroxy-17ubutenyl-l9-nor-androstene are preparedstarting respectively from the l7m-propyl-19-nor-testosterone and the1'7a-butenyl-19-nor-testosterone.

These compounds are converted in any manner known into the 17-esters'derived from saturated and unsaturated carboxylic acids.

Example II] To a solution of 5 g. of 3-eno1, 17-diacetate of19-nortestosterone in 200 ml. of ethyl acetate, 20 ml. of 1 Nperphthalic acid are added. The mixture is kept at room temperature for48 hours, after that washed out with a dilute sodium hydroxide solution,next with water and finally dried with sodium sulphate. The solution isafter that evaporated to dryness in vacuo and the residue crystallisedfrom a mixture of acetone and ether to obtain 3.4 g. of the A-3-keto-6,17-dihydroxy-19-nor-androstene- 17-acetate; melting point189-190 C. and [a] =58 (chloroform).

2 g. of this solution are dissolved in 200 ml. of acetone after which3.8 ml. of 2.4 N chromic acid are added to this solution. The mixture isthen diluted with water and after that extracted with methylenechloride. The extract is evaporated to dryness and the residuecrystallised from a mixture of acetone and ether to obtain the A -3,6diketo-l7-acetoxy-19-nor-androstene; melting point 169- 173 and [a]='-94 (chloroform).

l g. of this compoundis dissolved in 100 ml. of chloroform, after whichfor'one hour, at 0 C., HCl-gas is led through this solution. Thesolution is after that washed, dried and evaporated to dryness, afterwhich the residue is crystallised from a mixture of acetone and ether.There is obtained the A -3,G-diketo-17fl-acetoxy-19-nor-androstene;meltingpoint 191-1925 C. and [a] =|-108 (chloroform).

NafOH-solution the free compound is obtained.

To a solution of 1.6 g. of this compound in 11 ml. of pyridine 7 g. of,B-phenyl propionic acid anhydride are added. The reaction mixture isfurther treated as described in Example I to obtain the 17/3-phenylpropionate of the A -3,6-diketo-17,8-hydroxy-l9-nor-androstene.Analogously the trimethyl-acetate, the cyclopentyl propionate, thesuccinate, the caprylate and the decanoate are prepared.

Example IV In accordance with the manner described in Example I the17a-ethynyl-19-nor-testosterone is converted into the A 3,6 diketo 17,8hydroxy 17a ethynyl l9- nor-androstene via the3,17-diacetoxy-S-hydroxy-6-formoxy-17u-ethynyl-19-nor-androstane. To asolution of 0.8 g. of this compound in 60 ml. of ethanol 150 mg. Pd-BaSO (5%) catalyst are added. The solution is shaken in hydrogenatmosphere till 0.003 mol of hydrogen has been taken up. The catalyst isnext filtered off and the filtrate evaporated to dryness in vacuo. Theresidue is crystallised from acetonitrile to obtain the A -3,6-diketo-17fl-hydroxy-17a-vinyl-l9-nor-androstene.

This compound is converted in the manner described in the previousexamples into the 17-esters derived from acetic acid, caproic acid,fi-phenyl propionic acid and decane carboxylic acid.

In an analogous manner 17a-allyl-19-nor-testosterone and17a-propyl-19-nor-testosterone are converted into the corresponding A-6-keto-steroids.

Example V 5.4 g. of A -3 8,17 3-diacetoxy-l9-nor-androstene aredissolved in 54 ml. of formic acid, after which 6.4 ml. of hydrogenperoxide are added. The solution is left standing at room temperaturefor 20 hours, after which it is poured out into 300 ml. of water. Theprecipitate formed is filtered oil and crystallised from a mixture ofbenzene and petroleum ether to obtain the3,17-diacetoxy-5-hydroxy-6-formoxy-l9-nor-androstane; melting point 169-169.5 C. and [a] =-6l (chloroform).

5.4 g. of this compound are dissolved in 300 ml. of methanol, afterwhich a solution of 1.8 g. of sodium carbonate in m1. of water is added.The mixture is stirred for 15 hours at room temperature and evaporatedin vacuo to a small volume, after which the residue is poured out into400 ml. of water. The precipitate formed is filtered oil to obtain the3,17-diacetoxy-5,6-dihydroxy- 19-nor-androstane, which aftercrystallisation from acetone has a melting point of 224-225 C. and

(chloroform) 4 g. of this compound are dissolved in 400 ml. of acetone,cooled to 0 C., after which 7.5 ml. of 2.4 N

chromic acid are added. The reaction mixture is after that poured outinto water and extracted with methylene chloride, washed, dried andevaporated to dryness, after which the residue is crystallised fromethanol. There is obtained the3,l7-diacetoxy-5-hydroxy-6-keto-19-nor-an-- drostane; melting point209-210 C. and [a] =-79.

By saponification of this compound in the manner described in Example Ithe 3,5,17-trihydroxy-6-keto-19-norandrostane is obtained; melting point265-266 C. and 041 --48 (tetrahydrofuran) By oxidation of this compoundwith chromic acid in the manner described in Example I the3,6,l7-triketo-5- hydroxy-l9-nor-androstane is obtained; melting point218-219 C. and [a] "'=+58 (chloroform).

3.5 g. of this compound are dissolved in 350 ml. of chloroform, afterwhich HCl-gas is bubbled through at 0 C. The reaction mixture is workedup as described in Example I, after which the M-3,6,17-triketo-19-norandrostene is obtained; melting point 168-170 C.and [a] +223 (chloroform).

I claim:

1. New steroids of the general formula:

in which X is selected from the group consisting of a saturated andunsaturated hydrocarbon radical with 1-4 carbon atoms.

3. A -3,6-diketo-17p-hydroxy-17a-methyl-estrene.

4. A -3,6-diketo-17p-hydroxy-17a-ethyl-estrene.

References Cited in the file of this patent Zderic et aL: J.A.C.S. 81,3120-3124 (1959).

1. NEW STEROIDS OF THE GENERAL FORMULA: